It has already been shown that an increased amount of histamine is released during reflex dilatation evoked in the constantly perfused, innervated extremity of the dog, but the source of the reflexly released histamine has not been pinpointed. Experiments will be conducted by means of radiolabelled isotopes to determine if the histamine is distributed in the extravascular, extracellular space or in specialized depots. This will be done by use of the dual isotopic labeling technique. The rate of clearance of labeled histamine and of an extracellular space marker will be compared: a) with respect to time; and b) when blood flow to the extremity is intentionally varied by adjusting inflow rates. It is possible that inhibition of adrenergic tone may result in an increase in histamine release by altering the ratio of nutritive to non-nutritive flow. To explore this possibility varying amounts of norepinephrine, sufficient to replace adrenergic tone during reflex inhibition, will be infused intra-arterially. The effect of such infusions on the amount of histamine released during reflex dilatation will be determined. In other experiments the adrenergic nerves will be stimulated at varying intensities to evaluate the effect of adrenergic tone on the rate of clearance of radiolabeled histamine and an ECF marker. Studies on another form of dilatation referred to as sustained vasodilatation will be extended. By use of isotopic techniques, the amount of neurally released acetylcholine will be examined at various stages of the dilatation to determine if only the atropine sensitive portion of the dilatation elicited during lumbar sympathetic nerve stimulation following adrenergic amine depletion is mediated by acetylcholine. Attempts will be made to modify the sustained component of dilatation by administration of prostaglandin synthetase inhibitors. The possible release of prostaglandin during sustained dilatation will be examined by assay techniques. The interaction between the adrenergic and sustained dilator systems will be studied by a series of techniques involving electrical stimulation, administration of adrenergic amines, and agents which modify effective adrenergic discharge.